When partial or complete dysfunction of the kidney has occurred, wastes which must be excreted from the body as urine accumulate in the blood, and the electrolyte balance in the body is lost. As a method of remedying such renal failure symptoms, an extracorporeal circulation therapy using a hemodialyzer has been widely conducted in which wastes in blood are excreted from the body utilizing the diffusion/filtration principle and the electrolyte balance is adjusted.
A hemodialyzer is produced by incorporating a dialysis membrane in a housing and shaping the dialysis membrane so that mass transfer occurs between the blood and the dialysate through the dialysis membrane. Two compartments of a blood side compartment and a dialysate side compartment are formed in the housing through the dialysis membrane. The hemodialyzers are classified into a flat membrane type and a hollow fiber membrane type. At present, the hollow fiber membrane hemodialyzers are mainly used in which a tubular housing is filled with a hollow fiber membrane bundle and subjected to potting by providing a resin layer portion on each end of the hollow fiber membrane bundle. This is because the hollow fiber membrane hemodialyzer has a large contact area with blood and the dialysate in spite of its small volume as a whole to exhibit excellent mass transfer efficiency.
Various materials ranging from cellulose polymers to synthetic polymers are used for hollow fiber membranes utilized for hemodialyzers. In recent years, a polysulfone polymer has been mainly used as the membrane material since a membrane which shows excellent physical chemical stability and biological safety and exhibits a sharp molecular weight fractionation capability and excellent biocompatibility is easily obtained. However, since the surface of the resulting membrane exhibits too high a hydrophobicity when using only the polysulfone polymer, a small amount of hydrophilic polymer is practically used in combination with the polysulfone polymer. When using the two-component (multicomponent) membrane material prepared by adding the hydrophilic polymer to the polysulfone polymer, various hollow fiber membranes can be formed by adjusting the membrane forming conditions. This also makes the polysulfone polymer preferred as the membrane material.
Hemodialyzers with a blood contact membrane area of 0.1 m2 to 2.5 m2 are commercially available.
In dialysis facilities, a hemodialyzer with an optimum membrane area is selected from them depending on the physique, pathologic condition, treatment conditions, and the like of the target patient and used. Along with a demand for optimization of the treatment conditions and a further increase in the treatment efficiency, a hemodialyzer with a larger membrane area than conventional has been increasingly demanded in order to deal with various physiques of hemodialysis patients. In particular, a hemodialyzer with a large membrane area tends to be strongly demanded in Western countries because dialysis patients have a large physique on average. This is because a hemodialyzer with a large membrane area is suitable for the treatment of a dialysis patient who has a big physique and a large circulation blood volume, and certain treatment effects are expected to be achieved in a shorter period of time than conventional by causing blood or the dialysate to flow at a high flow rate.
However, the membrane areas of hemodialyzers with a large membrane area which have been put to practical use and are available as various products are limited to 2.2 m2 or less. As hemodialyzers with a membrane area exceeding 2.2 m2, only a cellulose triacetate hemodialyzer with a membrane area of 2.5 m2 and a polyarylethersulfone hemodialyzer with a membrane area of 2.4 m2 have been known. Furthermore, it is well known that the membrane material for the former hemodialyzer exhibits poor biocompatibility in comparison with the polysulfone. According to the finding of the inventors of the present invention, the latter hemodialyzer exhibits an insufficient dialysis performance for urea.
The inventors have got suspicious about the fact that polysulfone hemodialyzers with a large membrane area have not been put to practical use in spite of a great demand, and examined the relationship between the membrane area and the dialysis performance of commercially available polysulfone hemodialyzers for solutes with different molecular weights. As a result, the inventors have found that dialysis performance equivalent to the dialysis performance of hemodialyzers with a medium membrane area (about 1.3 to 1.8 m2) cannot be maintained when the membrane area of the hemodialyzer exceeds 2 m2. Uremic toxins with various molecular weights are contained in the blood of a renal failure patient. A hemodialyzer is required to exhibit solute removal capability of reducing all of these uremic toxins. A hemodialyzer is generally required to exhibit capability of removing uremic toxins ranging from urea with a molecular weight of 60 to β2-microglobulin with at least a molecular weight of 11,800 as much as possible. According to the finding of the inventors, however, the balance of the dialysis performance is significantly lost when the membrane area exceeds 2 m2. One hemodialyzer (crimped polysulfone hollow fiber membranes, peripheral type baffle with slits) exhibited excellent dialysis performance for β2-microglobulin with a high molecular weight, but exhibited insufficient dialysis performance for urea. Another hemodialyzer (spacer fibers twining polysulfone hollow fiber membranes, peripheral type baffle with sloping slits) exhibited excellent dialysis performance for vitamin B12 which is a medium molecular weight marker, but exhibited insufficient dialysis performance for urea. Yet another hemodialyzer (spacer fibers twining polyarylethersulfone hollow fiber membranes, peripheral type baffle) also exhibited insufficient dialysis performance for urea.
As described above, a tendency was observed in which it is difficult for polysulfone hemodialyzers to exhibit excellent dialysis performance over the molecular weight range of about 100 to 10,000 when the membrane area exceeds about 2 m2. Urea is the representative substance of uremic toxins and should be removed by a hemodialyzer. However, a polysulfone hemodialyzer with a membrane area exceeding 2 m2 exhibits insufficient dialysis performance for urea. It is considered that this point is one of the technical reasons which prevent a further increase in the membrane area.
The dialysis performance of the hemodialyzer is basically determined by the substance permeability of the individual hollow fiber membranes regardless of the membrane material. However, when several thousands of hollow fiber membranes are bound and filled in the hemodialyzer, a portion in which the dialysate does not sufficiently reach the surfaces of the membranes occurs in the hemodialyzer, whereby a nonuniform flow of the dialysate occurs. As a result, the hemodialyzer always suffers from a problem in which the individual hollow fiber membranes cannot maximally exhibit their inherent substance permeability. Therefore, it is necessary to improve and optimize the structure of the hemodialyzer in addition to the permeability of the dialysis membrane.
A number of studies have been conducted on the structure of the hemodialyzer for improving the dialysis performance in terms of the shape of the bundle, the shape of the housing, or the entire shape including the bundle.
Regarding the entire shape including the bundle, attempts have been made to increase the length of the housing with respect to the diameter of the housing. For example, patent documents 1 and 2 disclose technologies of improving the dialysis performance by increasing the ratio (L/D) of the length (L) and the diameter (D) of the housing. Patent document 3 discloses technology of increasing the ratio (L/D) by providing a swellable member which reduces the diameter of the major portion of the bundle in the housing.
However, when the membrane area is increased by the method of increasing the ratio (L/D) as disclosed in the patent documents 1 and 2, the length of the hemodialyzer must be increased. This increases the blood side and dialysate side pressure drop, whereby incensing the risk that the dialysate contaminant likely flows into the blood side due to hemolysis or reverse filtration. Though the diameter of the major portion of the bundle is reduced as disclosed in the patent document 3, reverse filtration of the dialysate increasingly occurs. Although the removal performance for proteins such as β2-microglobulin is improved, an improvement in the dialysis performance for low-molecular-weight solutes such as urea is not recognized.
Regarding the shape of the bundle, attempts have been made to provide a certain space between the hollow fiber membranes so that the hollow fiber membranes in the bundle do not adhere each other to form a dialysate channel. For example, patent document 4 discloses technology of preventing adhesion between the hollow fiber membranes by regularly twining spacer fibers around the hollow fiber membranes to provide a space. Patent documents 5 and 6 disclose technologies of providing a space between the hollow fiber membranes by geometrically crimping the hollow fiber membranes. In particular, the patent document 3 discloses that loading the housing with a bundle subjected to specific winding step reduces a local variation in dialysis performance for myoglobin (molecular weight: about 16,000) in the hemodialyzer, even if the same crimped hollow fiber membranes are used.
However, these technologies result in an increase in the diameter of the bundle or an increase in the size of the hemodialyzer. For example, the blood volume of the header is increased. Moreover, reverse filtration may be increased due to an increase of pressure drop in the dialysate side.
Regarding the shape of the housing, attempts have been made to allow the dialysate introduced through the dialysate inlet port to spread over the entire bundle without being retained or passing through a short path. For example, patent document 7 discloses a peripheral type baffle which is tapered toward the end of the hemodialyzer. The patent document 7 qualitatively demonstrates that the flow of the dialysate can be made uniform when the diameter of the bundle is partially increased along the tapered baffle. Patent documents 8 and 9 and non-patent document 1 disclose peripheral type baffles which generate a slit flow. In particular, the non-patent document 1 discloses that use of a peripheral type baffle provided with slits sloping to the hollow fiber membranes reduces a local variation in dialysis performance for vitamin B12 (molecular weight: 1,355) in the dialyzer.
However, any of these technologies complicate the structure of the housing. Moreover, when the diameter of the bundle is significantly increased along with an increase in the membrane area, the dialysate does not seem to reach the center portion of the bundle at a normal dialysate flow rate, for example.
As described above, when improving the shape of the bundle or the shape of the housing in addition to the entire shape, the dialysis performance is improved although some disadvantages occur due to an increase in the diameter of the bundle or a complicated housing structure. Therefore, some technologies have been put to practical use. However, the above technologies are successful for only hemodialyzers with a membrane area of about 1.5 to 1.6 m2. None of the above documents suggests application of the above technologies to hemodialyzers with a large membrane area exceeding 2.4 m2 and an improvement in dialysis performance for low-molecular-weight solutes.    [Patent document 1] JP-UM-B-57-53564    [Patent document 2] Japanese Patent No. 2961481    [Patent document 3] WO98/022161    [Patent document 4] JP-A-08-246283    [Patent document 5] WO01/60477    [Patent document 6] JP-A-2005-152295    [Patent document 7] JP-B-53-31828    [Patent document 8] JP-UM-B-07-37700    [Patent document 9] JP-A-2004-154772    [Non-patent document 1] Kidney and Dialysis (separate volume), High-performance Membrane 2004, pp. 33 to 36, Tokyo Igakusha Ltd